Several decades of animal research, and human studies showed a significant role of mechanical ventilation in the clinical outcome of patients with acute lung injury (ALl). But in some cases mechanical forces produced by ventilation cause further injury to the lung tissue, which increases morbidity and mortality in these patients. The proposed studies will identify the major gene(s) influencing differences in ventilator induced acute lung injury survival. Our Specific Aims are 1) to perform strain-specific survey of mouse susceptibility or resistance to ventilator induced ALl, 2) to identify quantitative trait loci (QTL) for ventilator induced ALl, 3) to identify via gene expression profiling of QTL region(s) found in aim 2 destructive and protective genes involved in ventilator induced ALl. We will utilize well-established murine mechanical ventilation model. In these studies, we will first challenge each strain with mechanical ventilation and evaluate the ALl responses and survival rate. Strains with the highest survival rate will be classified as resistant (n=3) and those with the lowest survival rate as susceptible strains (n=3). After these strains will be identified, we will phenotype FI, back-cross (BX), and F2 progeny derived from these strains. Then selected strains will be genotyped and data will be analyzed using Map Manager QTXb16. The QTLs identified by this approach will be explored in detail using gene expression profiling. Our studies could provide insight into the mechanisms through which mechanical ventilation triggers ALl. These studies could uncover novel targets for prophylactics and therapeutic protection against ventilator-induced ALl.